High-Performance Liquid Chromatography-Tandem Mass Spectrometry Method Development and Validation for Simultaneous Determination of Seven Nitrosamine and Azidomethyl-Biphenyl-Tetrazole Impurities in Losartan.

Nitrosamine-related impurities (N-nitrosomethylamino butyric acid [NMBA], N-nitrosodiethylamine [NDEA], N-nitrosodiisopropylamine [NDIPA], N-nitrosomethylphenylamine [NMPA], N-nitrosodibutylamine [NDBA], N-nitrosodimethylamine [NDMA], and N-nitrosoethylisopropylamine [NEIPA]) and 5-[4'-(azidomethyl)-[1,1'-biphenyl]-2-yl]-2H-tetrazole (AZBT) formed during the manufacture of sartan medicines have been classified into human mutagens and carcinogens after long-term treatment. The study developed a simple, economical but highly sensitive procedure for the simultaneous quantification of seven nitrosamines and AZBT impurities in sartan pharmaceuticals. After extraction with methanol (MeOH) 50%, the compounds were analyzed with a reversed-phase liquid chromatography-tandem mass spectroscopy with atmospheric-pressure chemical ionization (APCI) mode (APCI[+] for nitrosamines and APCI[-] for AZBT), selected reaction monitoring, C18 column, gradient elution with 0.1% formic acid in water and in MeOH, respectively. The validated procedure obtained high extraction efficiency (>90%), wide linear range (0.2-50.0 ng/mL NMBA, NDEA, NDIPA, NMPA, and NDBA; 0.5-50.0 ng/mL NDMA and NEIPA; 2.0-100 ng/mL AZBT), limit of quantification < 10% of the acceptance level, recovery range of 85%-115% with relative standard deviation < 15% and minimum matrix effects for all impurities. The procedure was applied to test 16 commercial losartan samples. As a result, eight samples contained AZBT within the current regulatory limits, but no nitrosamine impurities were detected in all samples.

Combination of Losartan and Platinum Nanoparticles with Photothermal Therapy Induces Immunogenic Cell Death Effective Against Neuroblastoma.

Introduction: Photothermal therapy (PTT) is a promising therapeutic procedure with minimal side effects, which can not only kill tumor directly but also cause immunogenic cell death (ICD). However, most solid tumors, including neuroblastoma, are abundant in fibroblasts, which limit the penetration and delivery of nanoparticles. Losartan is an antihypertensive drug approved by the FDA, and it has been proved to have the effect of breaking down excessive ECM network. Methods: In this study, we investigated the application and potential mechanism of the combination of mesoporous platinum nanoparticles (MPNs) and losartan in the PTT of neuroblastoma by establishing neuroblastoma models in vitro and in vivo. Results: Compared to the MPNs group without 808 nm laser irradiation, Neuro-2a cells pretreated with PTT and losartan showed lower survival rates, increased surface calreticulin, and higher release of HMGB1 and ATP. The group also exhibited the highest anti-tumor efficacy in vivo, with a tumor suppression ratio of approximately 80%. Meanwhile, we found that CD3+ T cells, CD4+ T cells and CD8+ T cells from the peripheral blood of experimental group mice were significantly higher than control groups, and CD8+PD-1+ cells were significantly lower than those in MPNs + Los group and Los + laser group. And the expression of PD-1 and α-SMA in Neuro-2a tumors tissue was reduced. Furthermore, losartan could reduce damage of liver function caused by MPNs and laser treatment. Conclusion: This study demonstrated that losartan-induced fibroblasts ablation increased the penetration of MPNs into tumors. Enhanced penetration allowed PTT to kill more tumor cells and synergistically activate immune cells, leading to ICD, indicating the great promise of the strategy for treating neuroblastoma in vivo.

IMPACT OF NEONATAL HYPEROXIA ON ADULT CARDIAC AUTONOMIC FUNCTION IN RATS: ROLE OF ANGIOTENSIN II TYPE 1 RECEPTOR ACTIVATION.

Individuals born preterm present altered cardiac autonomic function, a risk factor to heart diseases. Neonatal renin-angiotensin-system activation contributes to adult cardiomyopathy in rats exposed to neonatal hyperoxia, a well-established model of preterm birth-related conditions. Central angiotensin II receptor activation is a key modulator of the autonomic drive to the heart. Whether neonatal hyperoxia leads to alteration of the cardiac autonomic function through activation of the angiotensin II receptor type 1 (AT1) is unknown and was examined in the present study. Sprague-Dawley pups were exposed to hyperoxia or room air from postnatal days 3 to 10. AT1 antagonist losartan or water was given orally postnatal days 8 to 10. Blood pressure, autonomic function, left ventricular sympathetic innervation, ß-adrenergic-receptors expression, and AT1 expression in the solitary-tract-nucleus were examined in adult rats. Neonatal hyperoxia led to loss of day-night blood pressure variation, decreased heart rate variability, increased sympathovagal balance, increased AT1 expression in the solitary-tract, decreased left ventricle sympathetic innervation, and increased ß1-adrenergic-receptor protein expression. Losartan prevented the autonomic changes and AT1 expression in the solitary-tract but did not impact the loss of circadian blood pressure variation nor the changes in sympathetic innervation and in ß1-adrenergic-receptor expression. In conclusion, neonatal hyperoxia leads to both central autonomic and cardiac sympathetic changes, partly programmed by neonatal activation of the renin-angiotensin system.

Impact of Angiotensin Receptor Blockers (ARB) versus Other Antihypertensive Medication on Blood Pressure in Patients on Dialysis: A Meta-Analysis.

Introduction: Hypertension is an important factor driving mortality among dialysis patients. Angiotensin-II receptor blocker (ARB) has been effective similarly to angiotensin-converting enzymes (ACEs) but with a low incidence of side effects. Methodology: The meta-analysis included all published studies that investigated the effect of ARB on the hypertension in adult dialysis patients (≥18 years). Data extraction was guided by a predetermined checklist. Data sources of the retrieved studies were PubMed, MEDLINE, ScienceDirect, SCOPUS, Cochrane, Web of knowledge, and Google Scholar were systematically searched until February 2023. Using the RevMan 5 software, the mean difference for systolic and diastolic BP (SBP and DBP) and the risk ratio (RR) of the adverse events (AEs) were pooled from the selected studies. The random-effects model was used to compare the difference in the pre-and post-dialysis of the SBP and DBP. Data analyses were performed from December 2022 to February 2023. The primary outcome was the reduction in SBP and DBP in dialysis hypertensive patients who were on anti-hypertensive agents, and the secondary outcome was assessment of AE associated with the drug after dialysis (PROSPERO Registration: CRD42022355369). Results: The initial search yielded 1,679 records, of which 84 studies underwent full-text evaluation, which identified 13 studies and 1,462 patients. The pooled standard MD for losartan with other anti-hypertensive agents, where the pre-dialysis SBP was 0.17 (95% confidence interval [CI]: -0.21-0.55) and the post-dialysis was 0.35 (95% CI: -0.17-1.02); yet, both are statistically non-significant, implies that there was no difference between Losartan and ARB drugs regarding the effect on the SBP. Diastolic BP for predialysis was -0.01 (95% CI: -0.65-0.63) and post-dialysis was 0.03 (95% CI: -0.24-0.30) and statistically non-significant. AEs by the ARB agents were lower compared to other anti-antihypertensive agents (relative risk [RR]: 1.01; 95% CI: 0.59-1.75) and statistically non-significant. Conclusion: This systematic review and meta-analysis of RCT demonstrated that ARB and other anti-hypertensive medications had similar impacts on the treatment of hypertension.

Antihypertensive agent losartan promotes tongue squamous cell carcinoma cell proliferation via EGFR/ERK1/2/cyclin D1 signaling axis.

OBJECTIVE: To study the effects of losartan, an angiotensin II receptor blocker, in the SCC4 and SCC25 human tongue squamous cell carcinoma cell lines. METHODS: Cell proliferation was measured by MTS/PMS activity and trypan blue exclusion assays. The levels of the cell proliferation marker, cyclin D1, were analyzed by western blotting. Apoptosis was assessed by caspase-3 activation and Annexin V-FITC/propidium iodide double staining. Activation of epidermal growth factor receptor (EGFR) and ERK1/2 was validated by western blotting. RESULTS: Moderate concentrations of losartan enhanced the proliferation of SCC4 and SCC25 cells. However, high losartan concentrations induced apoptosis in SCC4 cells. Losartan activated the EGFR/ERK1/2/cyclin D1 signaling axis, which in turn promoted cell proliferation. Afatinib (EGFR inhibitor) and U0126 (ERK1/2 inhibitor) abolished losartan-induced cell proliferation. In contrast, UC2288 (p21 inhibitor) enhanced it. CONCLUSIONS: Losartan exhibited dual effects on tongue squamous cell carcinoma cells. Moderate losartan concentrations facilitated cell proliferation, whereas high concentrations induced cytotoxicity in tongue carcinoma cells.

Losartan in Situ Forming Gel as a New Treatment for Hypertrophic Scars.

Hypertrophic scars are defined as visible lesions formed by excessive wound healing that cause cosmetic and, in some cases, functional challenges in patients. This study aimed to assess the efficacy of intralesional injections of losartan-loaded in situ forming gel and compare it with the common treatment (triamcinolone) in preventing scar formation. The formulation was prepared using a thermosensitive PLGA-PEG-PLGA triblock copolymer. Ear scar tissue in rabbits represented the hypertrophic scar, and the animals were treated with three treatments in three groups. Nine weeks following the single treatment, images of the scars were obtained and quantitatively analyzed using ImageJ and light microscopy was used to evaluate the fibroblast cell number, vascularization, inflammation and collagen deposition and fibrosis in H&E-stained sample tissue. According to the results based on the ImageJ and the Vancouver criteria, the losartan in situ forming gel (F-LG) indicated significantly higher improving effects on decreased vascularity and pigmentation in comparison with triamcinolone (F-TA) and placebo as a control (F-Ctl), although the effect F-LG was almost similar to F-TA on pliability and scar height, and they were better than the control. Histological findings showed F-LG and F-TA have less inflammatory and fibroblast cells compared to F-Ctl. Also, results indicated the dermal layers of the F-TA and F-LG groups' scar were thinner, and the deposition of collagens was reduced compared to the control. Consequently, F-LG was found to be an effective treatment in reducing scarring and promoting wound healing.No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Comparison of the effects of losartan potassium and benazepril in the treatment of hypertensive patients with insulin resistance.

Objective: To compare the efficacy of losartan potassium (LP) and benazepril in the treatment of hypertensive patients with insulin resistance (IR). Methods: This is a retrospective analysis of the clinical data of 155 hypertensive patients with IR admitted to Shanghai Pudong New Area People's Hospital from March 2021 to March 2023. Of these 76 received LP treatment (LP group), and 79 received benazepril treatment (benazepril group). Blood pressure levels, blood glucose and insulin levels, treatment efficacy, and incidence of adverse reactions before and after the treatment in both groups were compared. Results: After the treatment, diastolic and systolic blood pressure in the two groups significantly decreased compared to pre-treatment levels (P<0.05), with no significant difference between the two groups (P>0.05). After the treatment, levels of fasting plasma glucose (FPG), 2-hours plasma glucose (2hPG), fasting insulin (FINS), 2-hours insulin (2hINS), and insulin sensitivity index (ISI) in both groups significantly decreased compared to pre-treatment levels (P<0.05), with no significant difference between the two groups (P>0.05). There was no significant difference in the total efficacy and the incidence of adverse reactions between the two groups (P>0.05). Conclusions: The efficacy of LP and benazepril in treating hypertension with IR is equivalent. Both are safe and can effectively lower blood sugar and insulin levels, alleviate IR, and lower blood pressure.

Effects of Losartan on Patients Hospitalized for Acute COVID-19: A Randomized Controlled Trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) down-regulates angiotensin-converting enzyme 2, potentially increasing angiotensin II. We hypothesized that losartan compared to usual care decreases mortality and is safe in patients hospitalized with coronavirus disease 2019 (COVID-19). We aimed to evaluate the effect of losartan versus usual care on 28-day mortality in patients hospitalized for acute COVID-19. METHODS: Eligibility criteria included adults admitted for acute COVID-19. Exclusion criteria were hypotension, hyperkalemia, acute kidney injury, and use of angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors within 7 days. Participants were randomized to losartan 25-100 mg/day orally for the hospital duration or 3 months or the control arm (usual care) in 29 hospitals in Canada and France. The primary outcome was 28-day mortality. Secondary outcomes were hospital mortality, organ support, and serious adverse events (SAEs). RESULTS: The trial was stopped early because of a serious safety concern with losartan. In 341 patients, any SAE and hypotension were significantly higher in the losartan versus usual care groups (any SAE: 39.8% vs 27.2%, respectively, P = .01; hypotension: 30.4% vs 15.3%, respectively, P < .001) in both ward and intensive care patients. The 28-day mortality did not differ between losartan (6.5%) versus usual care (5.9%) (odds ratio, 1.11 [95% confidence interval, .47-2.64]; P = .81), nor did organ dysfunction or secondary outcomes. CONCLUSIONS: Caution is needed in deciding which patients to start or continue using ARBs in patients hospitalized with pneumonia to mitigate risk of hypotension, acute kidney injury, and other side effects. ARBs should not be added to care of patients hospitalized for acute COVID-19. CLINICAL TRIALS REGISTRATION: NCT04606563.

The Impact of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Metabolic Rate in Drosophila melanogaster.

Evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) may increase metabolic rate by promoting thermogenesis, potentially through enhanced fat oxidation and improved insulin. More research is, however, needed to understand this intricate process. In this study, we used 22 lines from the Drosophila Genetic Reference Panel to assess the metabolic rate of virgin female and male flies that were either fed a standard medium or received lisinopril for one week or five weeks. We demonstrated that lisinopril affects the whole-body metabolic rate in Drosophila melanogaster in a genotype-dependent manner. However, the effects of genotypes are highly context-dependent, being influenced by sex and age. Our findings also suggest that lisinopril may increase the Drosophila metabolic rate via the accumulation of a bradykinin-like peptide, which, in turn, enhances cold tolerance by upregulating Ucp4b and Ucp4c genes. Finally, we showed that knocking down Ance, the ortholog of mammalian ACE in Malpighian/renal tubules and the nervous system, leads to opposite changes in metabolic rate, and that the effect of lisinopril depends on Ance in these systems, but in a sex- and age-specific manner. In conclusion, our results regarding D. melanogaster support existing evidence of a connection between ACEI drugs and metabolic rate while offering new insights into this relationship.

In Vitro Spectroscopic Investigation of Losartan and Glipizide Competitive Binding to Glycated Albumin: A Comparative Study.

Understanding the interaction between pharmaceuticals and serum proteins is crucial for optimizing therapeutic strategies, especially in patients with coexisting chronic diseases. The primary goal of this study was to assess the potential changes in binding affinity and competition between glipizide (GLP, a second-generation sulfonylurea hypoglycemic drug) and losartan (LOS, a medication commonly prescribed for hypertension, particularly for patients with concurrent diabetes) with non-glycated (HSA) and glycated (gHSAGLC, gHSAFRC) human serum albumin using multiple spectroscopic techniques (fluorescence, UV-visible absorption, and circular dichroism spectroscopy). The results indicated that FRC is a more effective glycation agent for HSA than GLC, significantly altering the albumin structure and affecting the microenvironment around critical amino acid residues, Trp-214 and Tyr. These modifications reduce the binding affinity of LOS and GLP to gHSAGLC and gHSAFRC, compared to HSA, resulting in less stable drug-protein complexes. The study revealed that LOS and GLP interact nonspecifically with the hydrophobic regions of the albumin surface in both binary (ligand-albumin) and ternary systems (ligand-albumin-ligandconst) and specifically saturate the binding sites within the protein molecule. Furthermore, the presence of an additional drug (GLP in the LOS-albumin complex or LOS in the GLP-albumin complex) complicates the interactions, likely leading to competitive binding or displacement of the initially bound drug in both non-glycated and glycated albumins. Analysis of the CD spectra suggests mutual interactions between GLP and LOS, underscoring the importance of closely monitoring patients co-administered these drugs, to ensure optimal therapeutic efficacy and safety.

Losartan alters osteoblast differentiation and increases bone mass through inhibition of TGFB signalling in vitro and in an OIM mouse model.

Excessive production of Transforming Growth Factor ß (TGFß) is commonly associated with dominant and recessive forms of OI. Previous reports have indicated that administration of TGFß-targeted antibodies maybe of potential therapeutic benefit to OI patients. However, direct targeting of TGFß is likely to cause multiple adverse effects including simulation of autoimmunity. In the current study we use patient-derived normal and OI fibroblasts, osteoblasts and OIM mouse models to determine the effects of Losartan, an angiotensin II receptor type 1 (AT1) antagonist, on TGFß signalling and bone morphology in OI. In OIM mice bred on a mixed background administration of 0.6 g/L losartan for 4 weeks was associated with a significant reduction in TGFß from 79.2 g/L in the control to 60.0 ng/ml following losartan (p < 0.05), reduced osteoclast activity as measured by CTX from 275.9 ng/ml in the control to 157.2 ng/ml following 0.6 g/L of losartan (p < 0.05) and increased cortical bone thickness (P < 0.001). Furthermore in OIM mice bred on a C57BL/6 background 0.6 g/L losartan increased trabecular bone volume in the tibiae (P < 0.05) and the vertebrae (P < 0.01), increased cortical bone thickness (P < 0.001) reduced the trabecular pattern factor (P < 0.01 and P < 0.001 for the tibiae and vertebrae respectively), reduced osteoclast (P < 0.05) and osteoblast (P < 0.01) numbers as well as reducing the area of bone covered by these cell types. Interestingly, losartan did not affect immune cells infiltrating into bone, nor did this drug alter TGFß signalling in normal or OI fibroblasts. Instead, losartan reduced SMAD2 phosphorylation in osteoblasts, inhibiting their ability to differentiate. Our data suggest that losartan may be an effective treatment for the bone-associated dysmorphia displayed in OI whilst minimising potential adverse immune cell-related effects.

Evaluation of pharmacokinetic herb-drug interaction of diabecon and losartan by UHPLC-MS/MS.

The diabecon is an ayurvedic herbal formulation that contains a mixture of herbs traditionally used as antidiabetic which is reported in the ayurvedic pharmacopeia of India and Indian Materia medica. The diabetic population has a common co-morbidity of hypertension for which losartan drug is commonly used for the treatment of hypertension. However, there is a lack of research on the pharmacokinetics interaction between diabecon and losartan. This research aims to investigate the influence of diabecon on the pharmacokinetics of losartan drugs in rats by establishing a highly sensitive ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-MS/MS) method. The method was validated according to the USFDA guidelines and was applied for the pharmacokinetic study. The lowest concentration of losartan detection in rat plasma was found to be 1 ng/mL and the accuracy and precision were within the linear range (1-1500 ng/mL). The results revealed that after 28 days of dosing diabecon, it has altered the pharmacokinetic parameters like area under the curve (AUC0-t), drug clearance (Cl/F), and rate of elimination (Ke) of losartan, which may happen due to enzyme induction. Although there was a change in the pharmacokinetic parameters of losartan when administered in the presence of diabecon, it was found to be nonsignificant in rats (p > 0.05). According to the best of our knowledge, this is the first article that discusses the pharmacokinetic herb-drug interaction between diabecon and losartan.

Implementing losartan potassium-laden pegylated nanocubic vesicles as a novel nanoplatform to alleviate cisplatin-induced nephrotoxicity via blocking apoptosis and activating the wnt/ß-catenin/TCF-4 pathway.

AIMS: Losartan potassium-laden pegylated nanocubic vesicles (LP-NCVs-PEG) have an intriguing kidney-targeted nanoplatform for acute renal injury via blocking apoptosis and activating wnt/ß-catenin pathway. MAIN METHODS: Utilizing a thin-film hydration methodology established on 42 full factorial design to produce LP loaded nanocubic formulations (LP-NCVs) which composed mainly from L-α-phosphatidylcholine and poloxamer. The optimization process was designed to select the formulation with maximum entrapment efficiency (EE %), maximum in-vitro drug release (Q8h), and minimum vesicle size (VS). The optimum formulation was then pegylated to obtain LP-NCVs-PEG formulation that shields NCVs from the harsh ecosystem of the stomach, improves their oral drug delivery performance and targets the proximal renal tubules with no systemic toxicity. Male albino rats were injected with Cisplatin (6 mg/kg, i.p.) alone or with LP-formulations (5 mg/kg/day). Kidney injury markers, inflammatory markers, apoptotic markers. Besides renal tissue expression of Wnt, ß-Catenin, GSK-3ß, renal RNA gene expression of TCF-4, LEF-1 and histopathology were also analyzed to display pharmacological study. KEY FINDINGS: The pharmacokinetics studies demonstrated that LP-NCVs-PEG boosted LP bioavailability approximately 3.61 times compared to LP oral solution. Besides LP-NCVs-PEG may have an intriguing kidney-targeted nanoplatform for acute renal injury via decreased renal toxicity markers, renal expression of LEF-1, GSK3-ß, caspase, TNF-α, NF-κB and TUNEL expression. Alternatively, increased renal tissue level of Bcl-2, wnt, ß-catenin and TCF-4. SIGNIFICANCE: LP-NCVs-PEG improved LP pharmacokinetics targeting the kidney and improved injury by activating wnt/ß-catenin/TCF-4 pathway, blocking apoptosis, inflammation and renal toxicity markers suggesting it might be successful nephroprotective adjuvant therapy.

Losartan as a Reproposing Therapeutic Agent in Acute Respiratory Distress Syndrome: Modulating Inflammatory Responses and Cytokine Production.

Seeking a new drug has become a significant milestone in drug discovery. However, it might not be immediately used in urgent situations or during a pandemic. Acute Respiratory Distress Syndrome (ARDS) contributes to mild-to-severe symptoms in patients due to cytokine storms, leading to morbidity and mortality. Hypertension is recognized as an independent risk factor for the severity of ARDS regarding to both ACE Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) treatment, although the precise mechanism remains unclear. In this study, murine macrophage cell lines (RAW264.7) and alveolar epithelial type II-like cell lines (A549) were utilized to investigate the effect of Losartan (LOS). LOS attenuated nitric oxide production in a dose-dependent manner and collectively reduced intracellular reactive oxygen species (ROS) compared to Diclofenac under LPS-stimulation conditions. For ADRS-mimicking conditions, LPS-induced inflammatory A549 cells were performed to monitor the effect of LOS. The results showed that LOS exhibited a protective effect by increasing cell viability and decreasing intracellular ROS levels. Notably, a high dose of LOS increased intracellular ROS levels. Moreover, LOS treatment downregulated NF-kappaB activation and AT1R at the protein level. Correspondingly, proinflammatory mediator cytokines (TNF-alpha and IL-8) were downregulated, but not IL-6, during LOS treatment. Hence, LOS may provide substantial benefits to ARDS patients by modulating proinflammatory cytokine production through AT1R downregulation and NF-kappaB inactivation. The mechanistic insight into LOS's anti-inflammatory effect holds promise for reducing mortality rates among ARDS patients.

Placental ischemia-upregulated angiotensin II type 1 receptor in hypothalamic paraventricular nucleus contributes to hypertension in rat.

Preeclampsia (PE) is associated with increased angiotensin II sensitivity and poor neurological outcomes marked by temporal loss of neural control of blood pressure. Yet the role of centrally expressed angiotensin II type 1 receptor (AT1R) within the paraventricular nucleus of the hypothalamus (PVN) in the PE model is not understood. In a PE rat model with reduced placental perfusion pressure (RUPP) induced on gestational day 14 (GD14), the PVN expression and cellular localization of AT1R were assessed using immunofluorescence and western blotting. The sensitivity of RUPP to acute angiotensin II infusion was assessed. AT1R was antagonized by losartan (100 µg/kg/day) for 5 days intracerebroventricularly (ICV). Hemodynamic data and samples were collected on GD19 for further analysis. RUPP upregulated (p < 0.05) mRNA and protein of AT1R within the PVN and lowered (p < 0.05) circulating angiotensin II in rats. RUPP increased neural and microglial activation. Cellular localization assessment revealed that AT1R was primarily expressed in neurons and slightly in microglia and astrocytes. Infusion of 100 ng/kg as bolus increased the mean arterial pressure (MAP in mmHg) in both RUPP and Sham. ICV losartan infusion attenuated RUPP-increased MAP (113.6 ± 6.22 in RUPP vs. 92.16 ± 5.30 in RUPP + Los, p = 0.021) and the expression of nuclear transcription factor NF-κB, tyrosine hydroxylase (TH), NADPH oxidase 4 (NOX4) and reactive oxygen species (ROS) in the PVN. Our data suggest that centrally expressed AT1R, within the PVN, contributes to placental ischemia-induced hypertension in RUPP rats highlighting its therapeutic potential in PE.

Losartan Treatment Reduces Esophageal Eosinophilic Inflammation in a Subset of Eosinophilic Esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven esophageal disorder. Connective tissue disorders (CTDs) and esophageal connective tissue alterations are associated with EoE. Therefore, angiotensin II type 1 receptor blockade with losartan, an accepted CTD treatment, is a potential EoE treatment. OBJECTIVE: We evaluated losartan's effects on esophageal pathology, symptoms, and safety in patients with EoE with and without a CTD in an open-label, non-placebo controlled multisite study. METHODS: Fifteen participants with EoE, aged 5 to 23 years, underwent treatment with per-protocol titrated doses of losartan in an open-label, 16-week pilot trial. Losartan was added to standard of care therapy and 14 patients completed the study. Eosinophil counts served as the primary end point, whereas we also assessed the EoE Histology Scoring System, Endoscopic Reference Scores, EoE Diagnostic Panel, and patient-reported outcomes. RESULTS: Esophageal eosinophilia was not reduced after losartan. The peak eosinophil count was not reduced for the proximal (median [interquartile range]: -3 [-22 to 3]; P = .49) and distal esophagus (median [interquartile range]: -18 [-39 to -1]; P = .23). There were no differences in losartan response in EoE with or without CTD (n = 7 and 8, respectively). Regardless, in a small subset of four participants esophageal eosinophilia was resolved with a concomitant reduction in EoE Histology Scoring System score and Endoscopic Reference Score. Across all subjects, the Pediatric EoE Symptom Score, Pediatric Quality of Life Inventory EoE Module, and EoE Diagnostic Panel improved after losartan (P < .05). CONCLUSIONS: Losartan treatment was associated with improved patient-reported outcome scores and EoE Diagnostic Panel biomarkers although without a reduction in esophageal eosinophilia overall. A subset of patients demonstrated improved histopathologic and endoscopic features that could not be tied to a specific feature predicting response to treatment.

Mechanistic insight into the photoconversion of losartan potassium mediated by different types of microplastics.

Nowadays the proliferation of microplastics (MPs) in aquatic environments and impacts on the fate of organic contaminants (OCs) has drawn sustained worldwide attention. In this study, we investigated the effects of different types and aging degrees of MPs, specifically polystyrene (PSMPs), polyethylene terephthalate (PETMPs), and polylactic acid (PLAMPs), on the photo-transformation of LSTPs. Our results revealed that the facilitation of LSTP photoconversion by PSMPs exhibited a positive linear relationship with aging degree. On the other hand, the effects of PETMPs with different oxidation levels on LSTP photoconversion were weak, while the contribution of PLAMPs decreased as aging increased. Characterizations, quenching and probing experiments showed the aging mechanisms and the generation of reactive oxygen species (ROS) converged among various MPs. Specifically, theoretical calculations, TOC and GC-MS were conducted to verify that in the PLA0-mediated systems, it was the intermediates of PLA0 that prevailed in promoting the photoconversion of LSTP. The aged PLA own have a large propensity to consume ROS, which diminished their promotion of LSTP degradation. This differd from the reactions involving PSMPs and PETMPs, where the microplastic particles themselves were the main drivers of the photoconversion process rather than intermediates.

Eco-friendly simultaneous estimation of atenolol and losartan potassium in spiked human plasma via synchronous fluorescence with sustainability assessment.

A green, sensitive, and fast spectrofluorimetric technique for the simultaneous determination of atenolol (ATN) and losartan potassium (LSR) was developed. The proposed technique relied on the implementation of a first derivative synchronous fluorescence spectroscopy for the determination of the investigated drugs simultaneously without pretreatment procedures. The synchronous fluorescence of both drugs was measured in methanol at Δλ of 100 nm, and the first derivative peak amplitudes (1D) were measured at 321 nm for ATN and 348 nm for LSR, each at the zero-crossing point of the other. The method was rectilinear over the concentration ranges of 100-1000 ng/mL and 50-500 ng/mL for ATN and LSR, respectively. The proposed technique was successfully applied for the determination of the studied drugs in their laboratory-prepared mixture and pharmaceutical formulations, demonstrating high mean recoveries of 100.54% for ATN and 100.62% for LSR, without interference from common excipients. The results were in good agreement with those obtained by the comparison method. Three recent greenness assessment tools, the Eco-Scale tool, the Green Analytical Procedure Index (GAPI) metric, and the Analytical GREEnness metric approach, were employed to affirm the greenness of the proposed method. The developed method was proven to be eco-friendly.

Age-Related Effects of AT1 Receptor Antagonist Losartan on Cognitive Decline in Spontaneously Hypertensive Rats.

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-ß1-42 (Aß1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aß1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.

Drug Release and Stability Study of Innovated Losartan Potassium and Rosuvastatin Calcium Fixed-dose Combination Tablet.

BACKGROUND: Patient adherence to therapy and compliance is always a challenge for care providers in the management of chronic disorders with multiple medications. OBJECTIVE: Our study focused on formulating concurrently prescribed ARB (Angiotensin Receptor Blocker), i.e., losartan potassium, and a cholesterol-lowering statin derivative, i.e., rosuvastatin calcium, in a fixed-dose combination tablet. METHODS: The drugs were selected based on the presence of synergism and variation in solubility characteristics. Trial batches with fixed concentrations of both active pharmaceutical ingredients (APIs) and varying quantities of different excipients were prepared by dry granulation technique and subjected to different quality control tests for tablets. Batch F5 was selected on the basis of in-process quality control data for the development of a drug release protocol. Experimental conditions were optimized. Based on the sink condition, phosphate buffer (pH 6.8) was selected as the dissolution medium. Simultaneous determination of both APIs in samples collected at predetermined time intervals was carried out using the RP-HPLC technique with acetonitrile, methanol, and water (20:25:55 v/v/v) as mobile phase. RESULTS: Complete dissolution of both APIs in the FDC tablet was achieved in 45 min in 900 mL of the selected medium. The in vitro drug release protocol was validated for accuracy and precision without interference with sample analysis. CONCLUSION: In this study, a validated, accurate, and robust dissolution testing method was developed for the newly formulated FDC tablet.